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Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG‐CoA reductase
Author(s) -
Pak Valeriy V.,
Koo Minseon,
Kim Min Jung,
Yang Hye Jeong,
Yun Lyubov,
Kwon Dae Young
Publication year - 2008
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.889
Subject(s) - peptide , cyclic peptide , chemistry , rational design , reductase , stereochemistry , peptide sequence , sequence (biology) , enzyme , biochemistry , combinatorial chemistry , computational biology , biology , gene , genetics
This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3‐hydroxy‐3‐methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head‐to‐tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion (“ V ” parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC 50 = 0.4 µM) showed a 1200‐fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC 50 = 484 µM) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides. Copyright © 2008 John Wiley & Sons, Ltd.